Effects of different doses of galanthamine, a long-acting acetylcholinesterase inhibitor, on memory in mice.
The effects of galanthamine, a long-acting acetylcholinesterase inhibitor, on passive avoidance and a modified Morris swim task were studied in mice. Lesions of the nucleus basalis magnocellularis (nBM) produced significant decreases in cortical choline acetyltransferase (ChAT) activity and profound deficits on the 24-h retention of a passive avoidance response and the reversal phase of the swim task. Galanthamine, administered 4 h before testing, improved performance of the two tasks in a dose-dependent fashion. In both tasks, galanthamine produced a U-shaped dose-response curve: the optimal dose was 3.0 mg/kg, IP on passive avoidance and 2.0 mg/kg on the swim task. The improvements in performance were not due to differences in motor activity or sensitivity to electric footshock. Behavioral tolerance did not occur from repeated doses of galanthamine; in fact, prior doses of galanthamine appeared to have a priming effect on later performance. In contrast to the effects in nBM-lesioned mice, galanthamine impaired performance of control mice on both tasks. Several characteristics of galanthamine suggest that it may be effective in treating the central cholinergic deficits in Alzheimer's disease: 1) its ability to attenuate cognitive deficits in nBM-lesioned mice, 2) its relatively long half-life, and 3) its lack of tolerance effects in mice during 2 weeks of repeated dosing.
Sweeney
J E
JE
Department of Environmental Health Sciences, Johns Hopkins University School of Public Health, Baltimore, MD 21205.
Bachman
E S
ES
Coyle
J T
JT
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D002540:Cerebral Cortex / Q000033:anatomy & histology; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D005702:Galantamine / Q000008:administration & dosage / Q000494:pharmacology*; D007051:Ibotenic Acid / Q000378:metabolism; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects
D002800:Cholinesterase Inhibitors; D005702:Galantamine; D007051:Ibotenic Acid